WO2001022998A1 - Stable calcitriol solution for packaging in vials - Google Patents
Stable calcitriol solution for packaging in vials Download PDFInfo
- Publication number
- WO2001022998A1 WO2001022998A1 PCT/US2000/026417 US0026417W WO0122998A1 WO 2001022998 A1 WO2001022998 A1 WO 2001022998A1 US 0026417 W US0026417 W US 0026417W WO 0122998 A1 WO0122998 A1 WO 0122998A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solution
- calcitriol
- antioxidant
- ppm
- oxygen
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
Definitions
- the invention relates to liquid calcitriol formulations, particularly calcitriol formulations for intravenous administration. More specifically, the invention relates to a calcitriol solution, and a method for preparing the solution, which is suitable for packaging into vials.
- Calcitriol also known as 9,10-Secocholesta-5,7,10(19)-triene-l,3,25-triol, l ⁇ ,25-dihydroxycholecalciferol, or l ⁇ ,25-dihydroxyvitamin D 3 , is the biologically active form of vitamin D 3 which promotes intestinal calcium transport and bone calcium resorption. It is formed in the kidney during the second of two successive hydroxylations of vitamin D, and is administered therapeutically for the treatment of vitamin D-dependent rickets, osteoporosis, hypocalcemia (particularly when associated with hypoparathyroidism), and calcium metabolism disorders associated with renal failure. Calcitriol is supplied commercially in two forms.
- Rocaltrol ® (calcitriol) capsules (Roche Labs) provide a solid form for oral administration
- Calcijex ® (calcitriol) (Abbott Labs)
- the intravenous solution is supplied as 1 ml ampules containing either 1 meg or 2 meg of calcitriol.
- the ampules are stored at 15-30° C (59-86° F) and are formed of amber glass to protect the solution from light.
- Calcitriol is a colorless compound which can be degraded by light and oxygen. Therefore, it is supplied in combination with a metal ascorbate salt antioxidant, such as sodium ascorbate, and a chelating agent.
- a metal ascorbate salt antioxidant such as sodium ascorbate
- the headspace of the calcitriol ampule is filled with nitrogen gas to provide an inert atmosphere.
- the solution retains some oxygen and the reaction of the metal ascorbate antioxidant with the residual oxygen ultimately causes the clear solution to turn yellow. Since drug products are periodically inspected for discoloration, a significant amount of therapeutically useful product is discarded due to antioxidant discoloration.
- a calcitriol composition which is stored in an ampule has previously been described by Conway et al. (U.S.
- ampule packaging is therefore used only when the physical and chemical stability of the contents requires it.
- the invention provides a therapeutic aqueous calcitriol solution which has a molecular oxygen concentration of less than about 1 ppm, and more preferably less than about 0.5 ppm or less, the solution being resistant to antioxidant discoloration.
- the invention also provides said solutions packaged into containers such as ampules or pharmaceutical vials. Suitable vials are those comprising a closure means comprising a septum (i.e., a closure means that is penetrable and self- sealing).
- the invention also provides a method for limiting discoloration of a therapeutic calcitriol solution by preparing the solution with water which has been purged of oxygen, to yield an oxygen concentration of less than 1 ppm, and more preferably less than about 0.5 ppm. Further, the invention also provides a novel dosage form for calcitriol comprising an aqueous calcitriol solution packaged in a pharmaceutical vial, such as the pharmaceutical vials described by Etheredge (U.S. Patent No.
- the stopper preferably being at least partially coated with an inert polymer, such as polytetrafluoroethylene (Teflon ® (polytetrafluoroethylene), DuPont ® , Wilmington, Delaware), so as to prevent chemical interaction between any of the other stopper components and the calcitriol solution.
- an inert polymer such as polytetrafluoroethylene (Teflon ® (polytetrafluoroethylene), DuPont ® , Wilmington, Delaware
- the inventor has discovered a method to stabilize the antioxidants responsible for the discoloration of a therapeutic calcitriol solution, thereby providing a solution which can be packaged into vials.
- calcitriol in vials, since the available molecular oxygen in the solution causes the antioxidant, which protects the drug from chemical degradation, to be degraded to form colored (usually yellow) compounds.
- the calcitriol solution is chemically stable in the presence of the antioxidant, it is perceived as being degraded when the solution turns yellow.
- calcitriol solutions prepared from water having a dissolved oxygen level of less than 1 part per million, and preferably less than about 0.5 parts per million undergo significantly less antioxidant degradation than conventional aqueous calcitriol solutions.
- the therapeutic calcitriol solution of the present invention can be packaged into ampules or into glass vials, most preferably vials of amber glass to protect the calcitriol from degradation by light.
- the concentration of calcitriol in the therapeutic solution is preferably from approximately 0.5 mcg/ml to approximately 3 mcg/ml, and most preferably about 1.0 mcg/ml to 2.0 mcg/ml.
- Glass vials that can be used for packaging the solution of the present invention are commonly used for packaging injectable solutions and are known to those of skill in the art. Examples of glass vials which can be used to package calcitriol intravenous solution dosage forms are described, for example, in U.S. Patent Number 5,230,429 (Etheredge, July 27, 1993).
- the vial typically has a closure means, usually a stopper, formed of rubber or other polymeric material, which allows a needle to be inserted therethrough into the vial without requiring that any glass be broken.
- a preferred stopper has an inert (e.g., polytetrafluoroethylene (Teflon ® , DuPont ® Wilmington, Delaware)) coating to prevent chemical interaction between the stopper components and the calcitriol solution.
- the closure or stopper is typically held securely in place by a metal over- cap, which in turn has an exterior cover used to seal the vial until its initial use.
- the polymer closure means comprises at least one septum, or thinner area of polymer material, preferably centered in the body of the closure means, through which a needle can be inserted to contact the solution. The solution can be drawn into the needle without glass particle hazard to either the patient or the health care provider.
- the present invention provides a calcitriol solution which resists discoloration when an antioxidant is present in the solution, and a method for preparing such a calcitriol solution, by lowering and maintaining the oxygen content of the solution to about 0.5 ppm or less prior to packaging.
- the calcitriol solution vial is prepared using Water for Injection, USP, which has been purged of essentially all oxygen, to a level of less than 0.5 parts per million, preferably in a closed top vessel.
- the closed top vessel is important to the invention, since an open top vessel allows trace oxygen from the atmosphere to redissolve in the water.
- the calcitriol solution is placed into a suitable vessel, where nitrogen is directed to flow through sintered dispersion heads located at or near the bottom of the liquid volume, with the only exit port being a vent for excess nitrogen.
- An inert atmosphere is also maintained above the solution throughout the process of mixing the solution, filling the solution into vials, and closure and sealing of vials to yield a final product with a dissolved oxygen content of less than 0.5 ppm and a headspace oxygen content of less than 0.5 ppm.
- Nitrogen for example, can be used to provide the inert atmosphere.
- a calcitriol solution prepared by the method of the present invention will comprise, for example, about 1 meg to about 2 meg calcitriol, in admixture with about 1,000 to 15,000 parts, or, for example, about 10 mg/ml, ascorbate antioxidant, about 8 to about 12,000 parts, or approximately 1 mg/ml, of a chelating agent, with approximately 400 to approximately 80,000, or approximately 4 mg, of a surfactant, and added water sufficient to produce the desired solution volume.
- the added water is Water for Injection, USP, which has been sparged with nitrogen in a closed top vessel to produce an oxygen concentration of less than about 1, and preferably less than about 0.5, parts per million.
- the solution is maintained at a pH of approximately 6.5 to 7.8 using dibasic and monobasic sodium phosphate.
- the solution is sparged with nitrogen or other noble gas, as described above, and as the vials are filled and sealed a suitable atmosphere is maintained (using nitrogen or other noble gas, for example) to keep the oxygen concentration level at or below 1 ppm, or more preferably below 0.5 ppm.
- a solution such as that described above, prepared by the method of the present invention can be stored at 15 to 30 ° C for a period of at least two years without exhibiting solution discoloration, discoloration being determined using APHA color standards by methods known to those of skill in the art.
- Example A color-stabilized, chemically stable, sterile, dilute aqueous calcitriol (l ⁇ ,25-dihydroxycholecalciferol ) solution packaged in amber glass vials having a rubber/teflon closure and metal over-cap was prepared by placing 3300 ml of Water for Injection, USP, at a temperature of 15-30° C, into a 45.5 liter Kimax ® solution bottle (No. 16144-087, VWR Scientific, Buffalo Grove, Illinois) having a vented cover. Nitrogen, NF, was sparged through the water using sintered diffusion devices to produce fine nitrogen bubbles through the bulk liquid. Sparging was continued until a dissolved oxygen concentration of 0.09 ppm was reached.
- Sodium chloride (45.6 grams) and edetate disodium, dihydrate (33.43 grams) were added, and mixed under a nitrogen blanket until dissolved (less than 5 minutes).
- Sodium phosphate, monobasic (54.7 grams) and sodium phosphate, dibasic (231 grams) were added and mixed under a nitrogen blanket until dissolved.
- Sodium ascorbate (303.9 grams) was added, and mixing continued for more than 2 minutes to provide a bulk solution.
- Vials were filled under nitrogen atmosphere, using parallel in-line nitrogen flushing. Each 2 ml amber glass vial received 1.25 ml of solution, and a stopper was loosely placed over the vial opening. Trays of filled and stoppered vials were placed in a lyophihzer to provide complete exchange of headspace atmosphere with nitrogen, and the stoppers were internally seated before the vials were exposed to the general atmosphere. An alternate method for sealing would place the vials within a zero oxygen tunnel such as that commercially available from Modified Atmosphere Packaging Systems (Des Plains, IL).
- the invention is described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within its scope.
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE60006558T DE60006558T2 (en) | 1999-09-29 | 2000-09-26 | STABLE SOLUTION OF CALCITRIOL FOR PACKAGING IN VIALS |
CA002388438A CA2388438A1 (en) | 1999-09-29 | 2000-09-26 | Stable calcitriol solution for packaging in vials |
MXPA02003162A MXPA02003162A (en) | 1999-09-29 | 2000-09-26 | Stable calcitriol solution for packaging in vials. |
AU76162/00A AU7616200A (en) | 1999-09-29 | 2000-09-26 | Stable calcitriol solution for packaging in vials |
EP00965443A EP1216057B1 (en) | 1999-09-29 | 2000-09-26 | Stable calcitriol solution for packaging in vials |
JP2001526207A JP2003510293A (en) | 1999-09-29 | 2000-09-26 | Stable calcitriol solution for vial packaging |
AT00965443T ATE253940T1 (en) | 1999-09-29 | 2000-09-26 | STABLE SOLUTION OF CALCITRIOL FOR PACKAGING IN VIALS |
NO20021402A NO20021402L (en) | 1999-09-29 | 2002-03-20 | Stable calcitriol solution for packing in ampoules |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/408,970 | 1999-09-29 | ||
US09/408,970 US6211169B1 (en) | 1999-09-29 | 1999-09-29 | Stable calcitriol solution for packaging into vials |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001022998A1 true WO2001022998A1 (en) | 2001-04-05 |
Family
ID=23618517
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/026417 WO2001022998A1 (en) | 1999-09-29 | 2000-09-26 | Stable calcitriol solution for packaging in vials |
Country Status (12)
Country | Link |
---|---|
US (1) | US6211169B1 (en) |
EP (1) | EP1216057B1 (en) |
JP (1) | JP2003510293A (en) |
AT (1) | ATE253940T1 (en) |
AU (1) | AU7616200A (en) |
CA (1) | CA2388438A1 (en) |
DE (1) | DE60006558T2 (en) |
ES (1) | ES2204692T3 (en) |
MX (1) | MXPA02003162A (en) |
NO (1) | NO20021402L (en) |
PT (1) | PT1216057E (en) |
WO (1) | WO2001022998A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016156147A1 (en) | 2015-03-27 | 2016-10-06 | Grünenthal GmbH | Stable formulation for parenteral administration of tapentadol |
WO2018055070A1 (en) | 2016-09-23 | 2018-03-29 | Grünenthal GmbH | Stable formulation for parenteral administration of tapentadol |
US11547678B2 (en) | 2011-03-04 | 2023-01-10 | Gruenenthal Gmbh | Aqueous pharmaceutical formulation of tapentadol for oral administration |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2406446A1 (en) * | 2000-09-18 | 2002-03-21 | Gregory Paul Handreck | Diphosphonate solutions |
HUP0501186A2 (en) * | 2001-12-03 | 2006-05-29 | Novacea | Pharmaceutical compositions comprising active vitamin d compounds |
US20040058895A1 (en) * | 2002-09-18 | 2004-03-25 | Bone Care International, Inc. | Multi-use vessels for vitamin D formulations |
US7148211B2 (en) * | 2002-09-18 | 2006-12-12 | Genzyme Corporation | Formulation for lipophilic agents |
US20040053895A1 (en) * | 2002-09-18 | 2004-03-18 | Bone Care International, Inc. | Multi-use vessels for vitamin D formulations |
US20050026877A1 (en) * | 2002-12-03 | 2005-02-03 | Novacea, Inc. | Pharmaceutical compositions comprising active vitamin D compounds |
US20060217316A1 (en) * | 2003-04-02 | 2006-09-28 | Ragab El-Rashidy | Method for the treatment of prostate cancer |
US20050020546A1 (en) * | 2003-06-11 | 2005-01-27 | Novacea, Inc. | Pharmaceutical compositions comprising active vitamin D compounds |
MX345215B (en) * | 2010-08-06 | 2017-01-19 | Hospira Australia Pty Ltd | Vial preparation method and system. |
WO2013114003A1 (en) * | 2012-01-30 | 2013-08-08 | Laboratoires Urgo | Method for preparing a syrupy product comprising vitamins |
WO2015119183A1 (en) * | 2014-02-05 | 2015-08-13 | 協和発酵キリン株式会社 | Liquid drug containing active vitamin d3 or derivative thereof |
CN116077432B (en) * | 2023-02-21 | 2023-09-08 | 正大制药(青岛)有限公司 | Calcitriol oral solution and preparation method thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4308264A (en) * | 1981-01-28 | 1981-12-29 | Abbott Laboratories | Stabilized, dilute aqueous preparation of 1α,25-dihydroxycholecalciferol for neonatal administration |
EP0294127A2 (en) * | 1987-05-29 | 1988-12-07 | Daikyo Gomu Seiko Ltd. | Resin-laminated rubber stopper |
JPH05238936A (en) * | 1992-02-27 | 1993-09-17 | Dainippon Pharmaceut Co Ltd | Aqueous liquid agent of calcitriol |
WO1996036340A1 (en) * | 1995-05-19 | 1996-11-21 | Abbott Laboratories | STABLE AQUEOUS FORMULATIONS OF 1α,25-DIHYDROXYCHOLECALCIFEROL FOR PARENTERAL ADMINISTRATION |
US6051567A (en) * | 1999-08-02 | 2000-04-18 | Abbott Laboratories | Low oxygen content compositions of 1α, 25-dihydroxycholecalciferol |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4420092A (en) | 1982-09-01 | 1983-12-13 | Mpl Inc. | Tamper-resistant pharmaceutical vial and cap assembly |
US5230429A (en) | 1990-12-13 | 1993-07-27 | Etheredge Iii Robert W | Tamper-evident injectable drug vial |
-
1999
- 1999-09-29 US US09/408,970 patent/US6211169B1/en not_active Expired - Fee Related
-
2000
- 2000-09-26 CA CA002388438A patent/CA2388438A1/en not_active Abandoned
- 2000-09-26 JP JP2001526207A patent/JP2003510293A/en active Pending
- 2000-09-26 AU AU76162/00A patent/AU7616200A/en not_active Abandoned
- 2000-09-26 EP EP00965443A patent/EP1216057B1/en not_active Expired - Lifetime
- 2000-09-26 PT PT00965443T patent/PT1216057E/en unknown
- 2000-09-26 DE DE60006558T patent/DE60006558T2/en not_active Expired - Fee Related
- 2000-09-26 AT AT00965443T patent/ATE253940T1/en not_active IP Right Cessation
- 2000-09-26 WO PCT/US2000/026417 patent/WO2001022998A1/en active IP Right Grant
- 2000-09-26 MX MXPA02003162A patent/MXPA02003162A/en active IP Right Grant
- 2000-09-26 ES ES00965443T patent/ES2204692T3/en not_active Expired - Lifetime
-
2002
- 2002-03-20 NO NO20021402A patent/NO20021402L/en not_active Application Discontinuation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4308264A (en) * | 1981-01-28 | 1981-12-29 | Abbott Laboratories | Stabilized, dilute aqueous preparation of 1α,25-dihydroxycholecalciferol for neonatal administration |
EP0294127A2 (en) * | 1987-05-29 | 1988-12-07 | Daikyo Gomu Seiko Ltd. | Resin-laminated rubber stopper |
JPH05238936A (en) * | 1992-02-27 | 1993-09-17 | Dainippon Pharmaceut Co Ltd | Aqueous liquid agent of calcitriol |
WO1996036340A1 (en) * | 1995-05-19 | 1996-11-21 | Abbott Laboratories | STABLE AQUEOUS FORMULATIONS OF 1α,25-DIHYDROXYCHOLECALCIFEROL FOR PARENTERAL ADMINISTRATION |
US6051567A (en) * | 1999-08-02 | 2000-04-18 | Abbott Laboratories | Low oxygen content compositions of 1α, 25-dihydroxycholecalciferol |
Non-Patent Citations (1)
Title |
---|
DATABASE WPI Section Ch Week 199342, Derwent World Patents Index; Class A96, AN 1993-331356, XP002156495 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11547678B2 (en) | 2011-03-04 | 2023-01-10 | Gruenenthal Gmbh | Aqueous pharmaceutical formulation of tapentadol for oral administration |
WO2016156147A1 (en) | 2015-03-27 | 2016-10-06 | Grünenthal GmbH | Stable formulation for parenteral administration of tapentadol |
EP3479823A1 (en) | 2015-03-27 | 2019-05-08 | Grünenthal GmbH | Stable formulation for parenteral administration of tapentadol |
US11013701B2 (en) | 2015-03-27 | 2021-05-25 | Grünenthal GmbH | Stable formulation for parenteral administration of tapentadol |
WO2018055070A1 (en) | 2016-09-23 | 2018-03-29 | Grünenthal GmbH | Stable formulation for parenteral administration of tapentadol |
US10898452B2 (en) | 2016-09-23 | 2021-01-26 | Gruenenthal Gmbh | Stable formulation for parenteral administration of Tapentadol |
Also Published As
Publication number | Publication date |
---|---|
NO20021402D0 (en) | 2002-03-20 |
ES2204692T3 (en) | 2004-05-01 |
EP1216057A1 (en) | 2002-06-26 |
CA2388438A1 (en) | 2001-04-05 |
PT1216057E (en) | 2004-04-30 |
JP2003510293A (en) | 2003-03-18 |
AU7616200A (en) | 2001-04-30 |
DE60006558T2 (en) | 2004-05-13 |
NO20021402L (en) | 2002-03-20 |
DE60006558D1 (en) | 2003-12-18 |
US6211169B1 (en) | 2001-04-03 |
ATE253940T1 (en) | 2003-11-15 |
EP1216057B1 (en) | 2003-11-12 |
MXPA02003162A (en) | 2003-08-20 |
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